Epigenetic regulation of chromatin determines how and when genetic information is used in a heritable way. Specific chromatin modifying proteins have profound effects on the chromatin landscape. Two recent surprises from the cancer genome atlas are of direct importance to this proposal: driver mutations in genes encoding proteins involved in epigenetic processes, and driver mutations in enzymes of central metabolism. Recent studies give us a peek into coordination between metabolism and the activity of histone modifying enzymes, and establish the principle that epigenetic processes are sensitive to changes in the metabolic state of a cell. The scope of this phenomenon and the precise mechanisms involved remain unclear despite its high relevance to cancer development and potential for new therapeutic strategies. Both metabolic and epigenetic dysregulation play a critical role in tumor development. This proposal seeks an understanding of both the scope and mechanism for how metabolism impacts genetic and epigenetic processes. The central hypothesis of this proposal is that changes in metabolism can affect the epigenetic landscape of a cell by altering the level of critical cofactors required by chromatin modifying enzymes and, in turn, the structures of chromatin determined by these modifications. Three aims are proposed: using Saccharomyces 1) elucidate links between central carbon metabolism and heterochromatin regulation, 2) identify the impact that accumulation of the cancer metabolite D-2-hydroxyglutarate has on gene silencing, and 3) comprehensively identify metabolic pathways that impact epigenetic processes. Results from this research will make a significant impact on our understanding of cellular processes governing epigenetic regulation, a fundamental aspect of genome biology. Of greatest importance, and in line with the goals of the National Institutes of Health, insight from this research will reveal key mechanisms that drive human diseases, particularly cancers, as well as open the door to new potential therapeutic strategies.